The compound 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (I) is known from WO2005026112 to possess anti Sirt1 activity, and as such useful in the preparation of medicaments for any condition which may benefit from the inhibition of Sirt1. These not limitedly include cancer, metabolic diseases such as metabolic syndrome, type I diabetes or type II diabetes, obesity, dislipidemia, hyperlipidemia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, neurodegenerative conditions that are caused at least in part by polyglutamine aggregation, such as Huntington's disease, spinalbulbar muscular atrophy (SBMA or Kennedy's disease) dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia 1 (SCA1), spinocerebellar ataxia 2 (SCA2), Machado-Joseph disease (MJD; SCA3), spinocerebellar ataxia 6 (SCA6), spinocerebellar ataxia 7 (SCAT), and spinocerebellar ataxia 12 (SCA12).
Compound (I) can be isolated, depending on the method of preparation, in crystalline form A or B or in amorphous form.
Form A is a solvent-free (FIG. 1), non hygroscopic (FIG. 2) form that can be obtained by crystallisation from isopropanol or by concentration at room temperature from various polar protic solvents such as methanol, ethanol, isopropanol or water, as well as from ethyl acetate. Form A is characterised by                an X ray diffraction pattern shown in FIG. 3 having prominent peaks as set out in table 1 below:        
TABLE 1°2θd space (Å)Intensity (%)11.37 ± 0.207.783 ± 0.1396913.26 ± 0.206.677 ± 0.1023116.50 ± 0.205.373 ± 0.0652717.76 ± 0.204.994 ± 0.0561922.02 ± 0.204.037 ± 0.0372922.77 ± 0.203.905 ± 0.03410024.18 ± 0.203.681 ± 0.0302924.54 ± 0.203.628 ± 0.02971                An IR absorbtion spectrum shown in FIG. 4 having characteristic peaks expressed in cm−1 at approximately 3448, 3307, 3277, 1649, 1306 and 772        A Raman spectrum shown in FIG. 5 having characteristic peaks expressed in cm−1 at approximately 3450, 3050, 1649, 1616, 1476, 1307, 1194, 901, 831, 323 and 197.        
(The term approximately means in this context that the values can vary, e.g. by up to ±4 cm−1)                A melting point of about 183° C.        
Form B (TGA and DSC curves in FIG. 6) is a non hygroscopic form (FIG. 7) that can be obtained by evaporation at room temperature from acetone or MEK (methyl ethyl ketone), or a mixture of solvents which contain acetone or MEK.
Form B is characterised by:                an X ray diffraction pattern shown in FIG. 8 having prominent peaks as set out in table 2 below        
TABLE 2°2θd space (Å)Intensity (%)10.86 ± 0.208.147 ± 0.1529014.73 ± 0.206.014 ± 0.0821815.42 ± 0.205.746 ± 0.0753517.19 ± 0.205.159 ± 0.0606717.91 ± 0.204.953 ± 0.0555121.27 ± 0.204.177 ± 0.0392821.69 ± 0.204.097 ± 0.0382522.50 ± 0.203.952 ± 0.0351824.18 ± 0.203.681 ± 0.0301525.50 ± 0.203.493 ± 0.027100                An IR absorbtion spectrum shown in FIG. 9 having characteristic peaks expressed in cm−1 at approximately 3389, 1683, 1405 and 1313        A Raman spectrum shown in FIG. 10 having characteristic peaks expressed in cm−1 at approximately 1712, 1623, 1485, 1313, 1163, 843, 339 and 212.        
(The term approximately means in this context that the values can vary, e.g. by up to +/−4 cm−1)                A melting point of about 165° C.        
The amorphous form of (I) is characterised by the lack of sharp X-ray diffraction peaks in its XRPD pattern (FIG. 11) and can be obtained by cryogrinding.
The amorphous form can easily be converted into form A or into form B. This can be achieved by slurrying in ethanol or acetone, towards forms A or B, respectively. In turn, form B can be easily converted into form A. This can be achieved by slurrying form B in water at various temperatures.
Form A is non hygroscopic (FIG. 2), stable over time (Tables 3 and 4) and it is suitable for use in pharmaceutical compositions.
Form A can be suitably formulated into various pharmaceutically acceptable preparations, which are preferably for oral administration.
A three-step method for the preparation of (I) is described in Napper et al. (“Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1.” Journal of Medicinal Chemistry 48.25 (2005): 8045-054.).

This method is however not amenable to large scale production. One drawback of the known method is the need for chromatographic purification of the intermediates. Another drawback is the use of ethyl ether as a solvent in the first step, which is hazardous on technical scale. Another major limiting factor is the presence of a highly exothermic second step, which is incompatible with the safety requirements of large scale production. Particularly, stage 2 of the process disclosed in Napper et al, wherein a compound of formula I′-a wherein R is ethyl is converted into a compound of formula I-b′ using unsolvated reactants, involves an uncontrollable exotherm which makes the process unsafe on a technical scale.
